It has been apparent for decades that the study of well defined human genetic disease, is a powerful tool in the elucidation of normal physiologic events. This Is most evident in the case of the primary immune deficiency diseases. Characterization of specific immune deficiency states has led to remarkable advances in immunology, catalyzing greater understanding of these diseases, and sparking the development of novel diagnostic techniques and targeted treatments. Studies of primary human B cell defects have led to an appreciation of specific stages of B cell development. Commitment to the B cell lineage occurs early In lymphogenesls with selected gene rearrangements in Ig heavy chain genes;these initiate the process of antigen recognition, a hall mark of adaptive immunity. Further maturation of B cells Is characterized by expansion, differentiation, trafficking to specific compartments in peripheral lymph nodes, selection of appropriate antigen receptors, the generation of B cell memory and finally population of mucosal sites. Coupled with the expansion of B cell populations, Is the requirement for deletion of self-reactive clones. All of these events are intertwined, but the nature of these interactions are Incompletely understood. The overall hypothesis of this Program Project Grant is that selected genetic, cellular and micro-environmental influences are critical to normal B cell development and that defects in any of these processes can result in Immune deficiency. This Program Project selects four specific stages of B cell immunity to Investigate, Project 1: Mechanisms of V(D)J Mediated Immunodeficiencies;Project 2: Investigating blocks to B cell memory;Projects: Regulation and function of IgA production in the intestinal mucosa;Project 4: Loss of B cell tolerance in primary immune deficiency. The development of normal protective immunity is essential for understanding vaccination, disease prevention, transplantation, and autoimmunity;yet how these immune responses are developed and controlled, require further elucidation. At Mount Sinai we have a unique and valuable resource in our Primary Immune Deficiency Program;this allows for careful study of selected stages of human B cell bioiogy, the subject of this Program Project Grant.